Address for correspondence
Venkata Ramana Malipeddi E-mail: drmvramana@gmail.com Funding sources none declared Conflict of interest none declared Received on August 27, 2017 Reviewed on December 18, 2017 Accepted on April 17, 2018
Abstract
Background. Ciprofloxacin is a broad-spectrum fluoroquinolone antibacterial drug to which most Gram-negative and many Gram-positive bacteria are highly susceptible. Fluoroquinolones are administe-red repeatedly, twice a day for 5 days, during the course of therapy. Hence, they require repeated administra-tion. Ciprofloxacin qualifies as a drug candidate for a controlled-release drug delivery system.
Objectives. The present work was aimed to develop ciprofloxacin hydrochloride-containing matrix tablets by the wet granulation method.
Material and methods. The tablets were prepared using EthocelTM 100 Premium and Eudragit® RS PO (Evonik Laboratory, Mumbai, India) as a rate-controlling polymer. Granular dioctyl phthalate (DCP) was used as a diluent. An isopropyl alcohol and dichloromethane (1:1) mixture was used as a granulating agent. The effect of the formulation variables on tablet performance was examined based on weight variation, hardness, friability, thickness, and drug release profiles. The results suggested that the tablets had good in-tegrity.
Results. The tablets were stable for 18 months. Formulation F7 gave a linear release pattern up to 12 h. The release of ciprofloxacin from formulation F7 followed zero-order kinetics. The release mechanism was found to be diffusion-controlled as the Higuchi equation was obeyed.
Conclusions. Ciprofloxacin hydrochloride-containing matrix tablets were prepared successfully. The ta-blets had good integrity and were found stable for 18 months.
Key words: ciprofloxacin hydrochloride, diffusion-controlled, EthocelTM 100 Premium, Eudragit® RS PO, matrix tablet
DOI
10.17219/pim/90020
Copyright
© 2017 by Wroclaw Medical University This is an article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Formulation and evaluation
of controlled-release matrix systems of ciprofloxacin
Venkata Ramana Malipeddi
1,A–F, Rajendra Awasthi
2,A–F, Kamal Dua
3,A–F1 Amity Institute of Pharmacy, Amity University, Lucknow, India 2 NKBR College of Pharmacy & Research Centre, Phaphunda, India
3 Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Australia
A – research concept and design; B – collection and/or assembly of data; C – data analysis and interpretation; D – writing the article; E – critical revision of the article; F – final approval of the article
Introduction
The rationale of designing an oral controlled release drug delivery system is to achieve a predetermined and
reproducible drug release profile from the system.1
Antibacterials are currently largely available on the mar-ket in the form of conventional dosage forms. Due to limitations in the use of conventional dosage forms, al-ternative dosage forms, such as sustained-release prod-ucts, have been developed. Such products are available on the market only for a few drugs of these categories. Many antibacterials are still used in conventional dos-age forms. There is a need to develop controlled-release drug delivery systems for these categories, so as to op-timize the therapy and accrue the numerous benefits of controlled-release drug delivery systems. Antibiotics are substances produced by various species of microor-ganisms that suppress the growth of other
microorgan-isms.2 Common usage often extends the term
“antibiot-ics” to include synthetic antimicrobial agents, such as sulfonamides and quinolones. The recent introduction of fluorinated 4-quinolones, such as ciprofloxacin and ofloxacin, represents an important therapeutic advance, since these agents have a broad antimicrobial activity and are effective after oral administration for the treat-ment of a wide variety of infectious diseases.3 Peak se-rum levels are obtained within 1–3 h after administering an oral dose of 200 mg, with peak levels ranging from 0.7 μg/mL (sparfloxacin) to 2.9 μg/mL (trovafloxacin).4 Fluoroquinolones are potent bactericidal agents against
Escherichia coli and various species of Salmonella, Shi-gella, Enterobacter, Campylobacter, and Niesseria.5
Ciprofloxacin is a broad-spectrum fluoroquino-lone antibacterial drug to which most Gram-negative bacteria and many Gram-positive bacteria are highly
susceptible.6 It has proven effective in the treatment
of many types of systemic infections as well as acute and chronic infections of the urinary tract.7 It is gener-ally well tolerated; however, ciprofloxacin may produce nausea, vomiting, diarrhea, and abdominal discomfort
after administration.8 The gastric irritation and dose
dumping problem of ciprofloxacin can be avoided by formulating a controlled-release drug delivery system. The oral dose of ciprofloxacin in adults is 500–750 mg for 12 h. The bioavailability of ciprofloxacin is 60–80%. The serum half-life for ciprofloxacin is 3.3 h. Fluoro-quinolones are administered repeatedly, twice a day for 5 days, during the course of therapy. Hence, they
re-quire repeated administration.9,10 Thus, ciprofloxacin
qualifies as a candidate for a controlled-release drug delivery system.
To overcome the limitations of immediate release for-mulations of ciprofloxacin hydrochloride, the purpose of the present study was to design and develop matrix sys-tems using EthocelTM and Eudragit® RS PO as a solubility retardant to maintain a sustained release profile.
Material and methods
Material
Ciprofloxacin hydrochloride was received as a gift sam-ple from Nicholas Piramal Ltd., Indore, India. EthocelTM 100 Premium and Eudragit® RS PO were received as a gift sample from Evonik Laboratory, Mumbai, India. Granular dicalcium phosphate (DCP) was received as a gift sample from Dhara Life Science Pvt. Ltd., Ahmedabad, India. Microcrystalline cellulose (Avicel PH 112) was received as a gift sample from NB Entrepreneurs, Nagpur, India. Croscarmellose sodium (Ac-Di-Sol) was received as a gift sample from Signet Chemical Corporation, Mumbai, India. Isopropyl alcohol and dichloromethane were purchased from Thomas Baker (Chemicals) Pvt. Ltd., Mumbai, India. Sodium starch glycolate, microcrystalline cellulose, so-dium lauryl sulfate, magnesium stearate, and purified talc were purchased from Nice Chemicals Ltd., Cochin, India.
Methods
Preparation of ciprofl oxacin hydrochloride matrix tablets
Ciprofloxacin hydrochloride and a 75% amount of Etho-cel 100 Premium and Eudragit RS PO were passed through #40 sieve and mixed thoroughly (Table 1). The remaining amount of the polymers was dissolved in 30 mL of an iso-propyl alcohol and dichloromethane (1:1) mixture. The resultant solution was used as a binding agent to prepare a wet mass. The wet mass was passed through #12 sieve to form granules. The wet granules were dried in a hot air oven at 45 ±5°C for 1 h. The dried granules were passed through #20 sieve and mixed with the remaining ingre-dients previously passed through #40 sieve. The granules were lubricated and compressed using a 19.5 × 10 mm size punch (capsule shape) in a rotary tablet press (Rimek Mini Press 1; Karnavati Engineering Ltd., Ahmedabad, India).
Preparation of conventional ciprofl oxacin hydrochloride tablets
The composition of the conventional tablets of cipro-floxacin is shown in Table 2. Ciprocipro-floxacin hydrochlo-ride, Avicel PH 112, sodium lauryl sulfate and Primojel® were passed through #40 sieve. Starch paste (10% w/w) was used as a binding agent. The wet mass was passed through #12 sieve and dried for 1 h. The dried granules were passed through #20 sieve. Lubricant and the other excipients were passed through #40 sieve and mixed with the dried granules for 5 min. The granules were com-pressed using a 16.4 × 8 mm size punch (capsule shape) in a rotary tablet press (Rimek Mini Press 1; Karnavati Engi-neering Ltd., Ahmedabad, India).
Evaluation of tablets
The tablets produced were characterized for weight variation, hardness using a Monsanto hardness Tester (PI-924, Slit Lamp KFCO International, Ambala, India), friability using a friabilator meeting United States Phar-macopeia (USP) requirements (EF-2; Electrolab, Mum-bai, India), and thickness using a Digital Vernier Caliper
(500-197-20, Mitutoyo, Japan).11,12 Each measurement
was done in triplicate.
The release study of ciprofloxacin hydrochloride from the prepared tablets was carried out using USP dissolu-tion apparatus II. The dissoludissolu-tion study was carried out in 900 mL of 0.1 N HCl (pH 1.2) for the initial 2 h and 900 mL phosphate buffer solution (PBS; pH 7.4) for the next 10 h at 100 rpm. The temperature was maintained at 37 ±0.5°C. Aliquots (5 mL) were withdrawn at every 1 h interval till the 12th h. The sink condition was maintained by replacing an equivalent amount of dissolution medium after each sampling. The samples were analyzed using
a ultraviolet (UV) spectrophotometer (UV 3000+;
LabIn-dia Instruments, Mumbai, InLabIn-dia) at 278 nm. The sampling was done in triplicate from each batch.13
To study the drug release behavior and kinetics, the dis-solution data was fitted in various kinetic models viz. zero-order (cumulative amount of drug released against time) and first-order kinetics (log cumulative percentage of drug
remaining against time). The drug release mechanism was investigated using Higuchi’s model (cumulative percent-age of drug released against the square root of time).14
Stability study
Stability studies on matrix tablets (formulations F4, F5 and F7) were carried out according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. Three tablets of each formulation were withdrawn, and observed visually for physical appearance (color or texture), drug content and dissolution profile at 0, 30th, 60th, 90th and 180th day. From the data, shelf life (t90%) was calculated.15
Results and discussion
Ciprofloxacin hydrochloride is water-soluble and it is rapidly and well absorbed from the gastrointestinal tract. The oral bioavailability of ciprofloxacin hydrochloride is 70%. Peak plasma concentration is obtained within 1–2 h and the plasma half-life of ciprofloxacin is 3–5 h. This results in rapid absorption and elimination of cip-rofloxacin hydrochloride from a conventional tablet. In order to control the release of the drug, rate-retarding
polymers, such as ethyl cellulose (EthocelTM 100
Pre-mium) and/or Eudragit® RS PO, were used in different
proportions. Nine formulations (F1–F9) were prepared as matrix tablets with individual polymers and mixtures of the 2 polymers. For comparison, 1 formulation (F10) was prepared by wet granulation method, using starch paste as a binding agent.
A spectrophotometric analytical method for ciproflox-acin was developed using distilled water as a solvent. The analytical wavelength of 278 nm was identified. The E1% solution gave 974. The molar extinction coefficient was 2.5 × 105. Beer-Lambert law was obeyed in the concentra-tion range 1–10 μg/mL. The R2 value (0.9998) proved the validity of the analytical method used.
The granules were evaluated for percent moisture con-tent. The moisture content was within acceptable lim-its. The tablets (formulations F1–F10) were evaluated for
Table 2. Composition of a conventional tablet of ciprofl oxacin hydrochloride (formulation F10)
Ingredients Quantity [mg/tablet]
Ciprofloxacin hydrochloride 580
Microcrystalline cellulose 140
Sodium lauryl sulphate 10
Sodium starch glycolate (Primojel®) 27
Starch (for paste in water) 60
Ac-Di-Sol 15
Magnesium stearate 6
Purified talc 6
Purified water q.s.
q.s. – quantum satis (enough).
Table 1. Composition of the matrix tablets of ciprofl oxacin hydrochloride (formulations F1–F9)
Ingredients Quantity [mg/tablet]
F1 F2 F3 F4 F5 F6 F7 F8 F9 Ciprofloxacin hydrochloride 580 580 580 580 580 580 580 580 580 EthocelTM 100 Premium 100 150 200 – 300 300 300 – – Eudragit® RS PO 200 150 100 300 – – – 300 300 Granular DCP 60 50 40 40 40 50 60 50 60 Avicel PH 112 40 50 60 60 60 50 40 50 40 Magnesium stearate 10 10 10 10 10 10 10 10 10 Purified talc 10 10 10 10 10 10 10 10 10 DCP – dioctyl phthalate.
physical integrity such as thickness, hardness, compres-sional weight, friability, and drug content. The results are presented in Table 3. The tablet surface was free of cracks and slumps. Weight variation is the major test to be checked frequently. Variation in the weight of the tablet leads to either undermedication or overdose. The average weight of the matrix tablets (formulations F1–F9) ranged from 980 to 1012 mg (expected weight of each tablet was 1000 mg). The weight of all tablets was within ±5% range of average weight. The average weight of the conventional tablet (formulation F10) was 855 ±5 mg (expected weight was 844 mg).
Friability decreased as the binder concentration in-creased. An increase in binder concentration will en-hance the formation of stronger inter-particulate bonds between the granules during compression. This means that the tablets would offer greater resistance to shock and abrasion since there is a stronger adhesive bonding of the granules at high binder concentrations. In general, tablets had good friability profiles (<0.8%).
The hardness of a tablet is an indication of its strength. The tablet should be stable to mechanical stress during han-dling and transportation. An increase in binder concentra-tion increased the hardness of the tablets. Hardness of the tablets (formulations F1–F10) varied from 6.0 to 7.5 kg/cm2. The hardness was satisfactory (5–10 kg/cm2) (Table 3).
Tablets should have uniform thickness and these values are used to adjust the initial stage of compression. The thickness of the tablets (formulations F1–F9) varied from 6.2 to 6.5 mm, which is permissible as per the standards (usually a range of ±5% around the average thickness is al-lowed). The thickness of the conventional tablets (formu-lation F10) ranged between 7.8 and 8.0 mm (Table 3). The thickness of all the formulations was found to be uniform.
The results showed that the disintegration time of the tablets increased from 5 ±0.17 to 11 ±0.52 min as the binder concentration increased from 0.25 to 1.0% (Table 3). The drug content was found to be in the range of 93.0–98.08%. The percentage moisture
content of the granules at the time of compression (6.1–8.3%) was satisfactory for compression of the cip-rofloxacin tablets. Drug content ranged from 96.4% to 96.6% of the expected drug content, which satisfies the compendial requirements. Thus, ciprofloxacin tablets with good physical integrity were obtained.
The in vitro release data of the 9 formulations (for-mulations F1–F9) are recorded in Fig. 1. Formulation F10 released 97.7% of the drug within 30 min of the dissolu-tion study and was unsuitable for controlled release. The results of the in vitro release study indicated that the re-lease of ciprofloxacin from 5 formulations (formulations F1, F2, F3, F6, and F10) was very fast (>80% in 2 h). Hence, these formulations were not suitable for controlled re-lease of ciprofloxacin. Formulations F4, F5, F7, F8, and F9 gave a linear release pattern of ciprofloxacin up to 12 h. The release rate was slow and incomplete from formula-tion F8 (63.35%) and F9 (43.05%) after 12 h of dissoluformula-tion study. Hence, formulations F8 and F9 were considered unsuitable for controlled release. Formulations F4, F5 and F7 showed a continuous and complete release of cip-rofloxacin up to 12 h (Fig. 1). A comparison of
regres-Fig. 1. In vitro release profi le of ciprofl oxacin hydrochloride from matrix tablets (formulations F1–F9) in 0.1 N HCl (pH 1.2) for initial 2 h and phosphate buff er
solution (PBS) (pH 7.4) for the next 10 h at 37 ±0.2°C (mean ± SD, n = 3)
Table 3. Physical and chemical parameters of the matrix tablets of ciprofl oxacin*
Parameter Formulations F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 Moisture content [% w/w] 7.40 ±1.03 7.30 ±0.57 6.90 ±0.65 7.30 ±0.97 6.87 ±1.51 5.93 ±0.85 6.50 ±1.06 6.00 ±0.96 5.69 ±1.13 6.10 ±0.82 Thickness [mm] 6.40 ±0.52 6.25 ±1.24 6.50 ±1.61 6.12 ±1.30 6.30 ±0.87 6.40 ±1.25 6.40 ±1.25 6.20 ±0.82 6.40 ±1.73 7.90 ±1.53 Hardness [kg/cm2] 6.5 ±1.57 7.0 ±2.51 6.5 ±1.52 6.0 ±0.84 6.5 ±0.72 7.0 ±1.18 7.1 ±1.92 7.5 ±1.23 6.7 ±0.85 6.5 ±0.79 Compressional wt [mg] (practical) 990 ±5.39 987 ±7.64 992 ±5.95 980 ±6.91 997 ±5.86 984 ±9.57 1002 ±13.27 1008 ±11.82 1012 ±9.82 852 ±10.28 Friability [%] 0.32 ±0.002 0.14 ±0.001 0.47 ±0.01 0.38 ±0.95 0.48 ±0.11 0.56 ±0.06 0.68 ±0.15 0.71 ±0.08 0.73 ±0.14 0.65 ±0.07 Drug content [%] 98.20 ±4.67 96.50 ±7.61 98.90 ±5.62 98.70 ±3.52 98.50 ±2.64 99.60 ±4.18 98.70 ±4.09 97.35 ±5.84 96.05 ±3.61 97.08 ±5.57 * The average of 10 determinations were given and the values are rounded off to a significant decimal.
sion equations of zero-order for formulations F4, F5 and F7 (Fig. 2) revealed that the slope and regression coef-ficient (R2) values for formulation F7 were higher when compared to formulations F4 and F5 and the intercept value (constant) was less for formulation F7 than for for-mulations F4 and F5. The x coefficient value was higher for formulation F7. Based on these results, formulation F7 was selected as the best. The regression graphs and equations of the zero-order release for F4, F5 and F7 are shown in Fig. 2. These results indicate that formulation F7 of the ciprofloxacin matrix tablets gave consistent re-lease of ciprofloxacin up to 12 h.
The in vitro release of ciprofloxacin from the selected formulation (F7) was analyzed for determination of the release kinetics. The data was processed into graphs to elucidate the linear relationship, i.e., kinetic principles. The regression analysis was done using Microsoft Excel statistical functions (Microsoft, Redmond, USA). The equations are given below:
Zero-order:
y = 8.1937 t + 7.1653; n = 12; R2 = 0.9847 First-order:
y = 0.0760 log t + 1.215; n = 12; R2 = 0.8606 As per the above equations, the release of ciprofloxa-cin hydrochloride followed zero-order kinetics, as the R2 value was higher for zero-order than for first-order.
The release of ciprofloxacin from the matrix tablets was expected to be diffusion-rate-controlled. Hence, the data was processed as per the Higuchi equation. The regres-sion equation for the data is given below:
Higuchi equation:
y = 37.936 t1/2 + 32.043; n = 12; R2 = 0.9901 The high R2 value indicates that the release mechanism of ciprofloxacin from the matrix tablets was diffusion-controlled.
Stability studies on the matrix tablets (formulations F4, F5 and F7) were carried out according to the ICH guide-lines. Three tablets of each formulation were withdrawn, observed visually for physical appearance and analyzed for drug content at 0, 30th, 60th, 90th, and 180th day. All tab-lets retained physical integrity and no visual differences in color or texture were observed. The average drug con-tent of the matrix tablets remaining at different intervals of time for each of the 3 formulations is shown in Table 4. From the data, shelf life (t90%) was calculated. The stabil-ity data from Table 4 (time vs % of drug remaining) for formulations F4, F5 and F7 was processed into graphs us-ing Microsoft Excel (Miscosoft, Redmond, USA) and re-gression equations were calculated for each formulation (Fig. 3). Degradation of ciprofloxacin followed first-order kinetics, as the regression coefficient value of the first-order plot was higher.
From the first-order plots, k values were calculated and substituted in the shelf life equation. The calculated val-ues are given in Table 5. Percent drug content at 0 time and after 180 days was taken as C0 and C (Table 5).
Fig. 2. Regression analysis of in vitro release data for the selected matrix tablets of ciprofl oxacin hydrochloride (formulations F4, F5 and F7)
Fig. 3. Degradation profi les of ciprofl oxacin hydrochloride tablets (formulations F4, F5 and F7)
Table 4. Results of stability study of ciprofl oxacin matrix tablets (formulations F4, F5 and F7) Time [days] Quantity (mg/tablet) F4 F5 F7 [mg] % [mg] % [mg] % 0 580 100 580 100 580 100 30 572.6 98.72 571.5 98.53 572.3 98.68 60 569.0 98.11 568.7 98.05 569.1 98.12 90 565.6 97.52 565.1 97.43 565.8 97.55 180 560.9 96.7 559.9 96.53 561.3 96.78
Table 5. Shelf life (t90%) of matrix tablet formulations of ciprofl oxacin hydrochloride (formulations F4, F5 and F7)
Formulation K × 10–4 t
90% [days]
F4 1.861 565
F5 1.960 547
The results of the stability study of the 3 formulations of ciprofloxacin matrix tablets revealed that these for-mulations are stable for a minimum period of 1.5 years. Analysis of the results gave significant observations, which were discussed in the light of current concepts and interrelationships among the other experimental results.
Conclusions
Ciprofloxacin hydrochloride-containing matrix tablets were prepared successfully. The tablets had good integrity and were stable for 18 months. Formulation F7 gave a lin-ear release pattern up to 12 h. The release of ciprofloxacin from formulation F7 followed zero-order kinetics. The re-lease mechanism was found to be diffusion-controlled as the Higuchi equation was obeyed.
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